Our research is focused on two major topics virus-host cell interactions and the regulation of protein synthesis. These topics are interrelated by our interest in the interferon (IFN)-induced protein kinase, PKR. In a virus-infected cell, PKR functions to shut down the production of new proteins, effectively stopping viral replication. In an uninfected cell, PKR functions as a tumor suppressor, playing a role in cellular growth control by regulating protein synthesis. Our primary objectives are to understand the strategies used by certain viruses to repress PKR, and to evaluate the role of PKR in the control of cell growth and in the development of malignancy. We have shown that hepatitis C virus (HCV) inhibits PKR through the action of the viral NS5A protein, suggesting a mechanism for the widespread resistance of HCV to IFN therapy. We also found that influenza virus represses PKR by activating a cellular PKR inhibitor, termed P58IPK. A better understanding of the mechanis ms used by these viruses to inhibit PKR may contribute to the development of novel antiviral therapeutics. Our studies on cellular growth control have shown that overexpression of P58IPK results in the formation of tumors owing to a combination of PKR-dependent and -independent processes. We have shown that P58IPK is regulated by a novel protein, designated P52rIPK, and by heat shock protein 40 (hsp40). We have also shown that P58IPK interacts with and modulates the activity of the molecular chaperone, hsp70, suggesting that P58IPK is part of a general stress-response pathway. Finally, we made considerable progress in the development and use of cDNA microarrays to examine the effects of HIV-1 and influenza virus infection on cellular gene expression. By enabling us to evaluate the expression patterns of thousands of genes simultaneously, microarrays provide a state-of-the-art approach to the study of virus-host cell interactions. FUNDING NIH grants AI-22646, AI-41629, and RR-0016 and by a grant from the Gustavus and Louise Pfeiffer Research Foundation. Gale, M. Jr., Blakely, C.M., Hopkins, D.A., Melville, M.W., Wambach, M., Romano, P.R., and Katze, M.G. Regulation of interferon-induced protein kinase PKR modulation of P58IPK inhibitory function by a novel protein, P52rIPK. Mol. Cell. Biol. 18 859-871, 1998. Gale, M. Jr., Blakely, C.M., Kwieciszewski, B., Tan, S-L., Dossett, M., Korth, M.J., Polyak, S.J., Gretch, D.R., and Katze, M.G. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein molecular mechanisms of kinase regulation. Mol. Cell. Biol. 18 5208-5218, 1998. Gale, M. Jr. and Katze, M.G. Molecular mechanisms of interferon resistance mediated by viral-directed inhibition of PKR, the interferon-induced protein kinase. Pharmacol. Ther. 78 29-46, 1998. Gale, M. Jr., Korth, M.J., and Katze, M.G. Repression of the PKR protein kinase by hepatitis C virus a potential mechanism for interferon resistance. Clin. Diag. Virol. 10 157-162, 1998. Korth, M.J., Taylor, M.D., and Katze, M.G. Interferon inhibits the replication of HIV-1, SIV, and SHIV chimeric viruses by distinct mechanisms. Virology 247 265-273, 1998. Melville, M.W., Tan, S-L., Wambach, M., Song, J., Morimoto, R.I., and Katze, M.G. The cellular inhibitor of the PKR protein kinase, P58IPK, is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity. J. Biol. Chem. 274 3797-3803, 1999. Romano, P.R., Zhang, R., Tan, S-L., Garcia-Barrio, M.T., Katze, M.G., Dever, T.E., and Hinnebusch, A.G. Inhibition of double-stranded RNA-dependent protein kinase PKR by vaccinia virus E3 role of complex formation and the E3 N-terminal domain. Mol. Cell. Biol. 18 7304-7316, 1998. Tan, S-L., Dossett, M., and Katze, M.G. Cryopreserved yeast cells suitable for routine, small-scale transformations. BioTechniques 25 792-793, 1998. Tan, S-L., Gale, M.J. Jr., and Katze, M.G. Double-stranded RNA-independent dimerization of interferon-induced protein kinase PKR and inhibition of dimerization by the cellular P58IPK inhibitor. Mol. Cell. Biol. 18 2431-2443, 1998. Tan, S-L. and Katze, M.G. Biochemical and genetic evidence for complex formation between the influenza A virus NS1 protein and the interferon-induced PKR protein kinase. J. Interferon Cytokine Res. 18 757-766, 1998. Tan, S-L. and Katze, M.G. Using genetic means to dissect homologous and heterologous protein-protein interactions of PKR, the interferon-induced protein kinase. Methods Companion Methods Enzymol. 15 207-223, 1998. Taylor, M.D., Korth, M.J., and Katze, M.G. Interferon treatment inhibits the replication of simian immunodeficiency virus at an early stage evidence for a block between attachment and reverse transcription. Virology 241 156-162, 1998.